Optimizing treatment with Bcr-Abl tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia: focus on dosing schedules. 2008

Elias Jabbour, and Jorge E Cortés, and Hagop Kantarjian
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. ejabbour@mdanderson.org

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), a genetic aberration that codes for bcrabl, which plays a key role in disease pathophysiology. The first oral inhibitor of Brc-Abl was imatinib, which also targets KIT and platelet-derived growth factor receptor kinase and has demonstrated improved outcomes when compared with interferon, the previous standard of care. Imatinib resistance and intolerance have been an issue for patients, and as a result, new therapeutic approaches have been evaluated. Dose-escalated imatinib (800 mg daily) has shown some limited activity in patients with imatinib-resistant CML, but the development of second-generation tyrosine kinase inhibitors has broadened the treatment options. Dasatinib is also an oral kinase inhibitor, but it has increased potency for Brc-Abl compared with imatinib. Dasatinib has demonstrated activity in all phases of CML and Ph+ acute lymphocytic leukemia and is approved for the treatment of adults in this setting. Recent phase III data have demonstrated that, in patients with chronic-phase CML, dasatinib 100 mg once daily is equally effective, with improved tolerability, compared with the previously approved 70-mg twice-daily dose. Nilotinib, which has been recently approved, has increased potency for Brc-Abl compared with imatinib and has demonstrated activity in patients with imatinib-resistant and -intolerant chronic- and accelerated-phase CML. As experience with these agents continues to mature, we might optimize the treatment efficacy and safety profiles by altering dose regimens.

UI MeSH Term Description Entries
D010677 Philadelphia Chromosome An aberrant form of human CHROMOSOME 22 characterized by translocation of the distal end of chromosome 9 from 9q34, to the long arm of chromosome 22 at 22q11. It is present in the bone marrow cells of 80 to 90 per cent of patients with chronic myelocytic leukemia (LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE). Ph1 Chromosome,Ph 1 Chromosome,1 Chromosomes, Ph,Chromosome, Ph 1,Chromosome, Ph1,Chromosome, Philadelphia,Chromosomes, Ph 1,Chromosomes, Ph1,Ph 1 Chromosomes,Ph1 Chromosomes
D011505 Protein-Tyrosine Kinases Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors. Tyrosine Protein Kinase,Tyrosine-Specific Protein Kinase,Protein-Tyrosine Kinase,Tyrosine Kinase,Tyrosine Protein Kinases,Tyrosine-Specific Protein Kinases,Tyrosylprotein Kinase,Kinase, Protein-Tyrosine,Kinase, Tyrosine,Kinase, Tyrosine Protein,Kinase, Tyrosine-Specific Protein,Kinase, Tyrosylprotein,Kinases, Protein-Tyrosine,Kinases, Tyrosine Protein,Kinases, Tyrosine-Specific Protein,Protein Kinase, Tyrosine-Specific,Protein Kinases, Tyrosine,Protein Kinases, Tyrosine-Specific,Protein Tyrosine Kinase,Protein Tyrosine Kinases,Tyrosine Specific Protein Kinase,Tyrosine Specific Protein Kinases
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D002986 Clinical Trials as Topic Works about pre-planned studies of the safety, efficacy, or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. This concept includes clinical trials conducted both in the U.S. and in other countries. Clinical Trial as Topic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000069439 Dasatinib A pyrimidine and thiazole derived ANTINEOPLASTIC AGENT and PROTEIN KINASE INHIBITOR of BCR-ABL KINASE. It is used in the treatment of patients with CHRONIC MYELOID LEUKEMIA who are resistant or intolerant to IMATINIB. (18F)-N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide,BMS 354825,BMS-354825,BMS354825,N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide,Sprycel,354825, BMS
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole
D015464 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Clonal hematopoetic disorder caused by an acquired genetic defect in PLURIPOTENT STEM CELLS. It starts in MYELOID CELLS of the bone marrow, invades the blood and then other organs. The condition progresses from a stable, more indolent, chronic phase (LEUKEMIA, MYELOID, CHRONIC PHASE) lasting up to 7 years, to an advanced phase composed of an accelerated phase (LEUKEMIA, MYELOID, ACCELERATED PHASE) and BLAST CRISIS. Granulocytic Leukemia, Chronic,Leukemia, Granulocytic, Chronic,Leukemia, Myelocytic, Chronic,Leukemia, Myelogenous, Chronic,Leukemia, Myeloid, Chronic,Myelocytic Leukemia, Chronic,Myelogenous Leukemia, Chronic,Myeloid Leukemia, Chronic,Leukemia, Chronic Myelogenous,Leukemia, Chronic Myeloid,Leukemia, Myelogenous, Ph1 Positive,Leukemia, Myelogenous, Ph1-Positive,Leukemia, Myeloid, Ph1 Positive,Leukemia, Myeloid, Ph1-Positive,Leukemia, Myeloid, Philadelphia Positive,Leukemia, Myeloid, Philadelphia-Positive,Myelogenous Leukemia, Ph1-Positive,Myeloid Leukemia, Ph1-Positive,Myeloid Leukemia, Philadelphia-Positive,Chronic Granulocytic Leukemia,Chronic Granulocytic Leukemias,Chronic Myelocytic Leukemia,Chronic Myelocytic Leukemias,Chronic Myelogenous Leukemia,Chronic Myelogenous Leukemias,Chronic Myeloid Leukemia,Chronic Myeloid Leukemias,Granulocytic Leukemias, Chronic,Leukemia, Chronic Granulocytic,Leukemia, Chronic Myelocytic,Leukemia, Ph1-Positive Myelogenous,Leukemia, Ph1-Positive Myeloid,Leukemia, Philadelphia-Positive Myeloid,Leukemias, Chronic Granulocytic,Leukemias, Chronic Myelocytic,Leukemias, Chronic Myelogenous,Leukemias, Chronic Myeloid,Leukemias, Ph1-Positive Myelogenous,Leukemias, Ph1-Positive Myeloid,Leukemias, Philadelphia-Positive Myeloid,Myelocytic Leukemias, Chronic,Myelogenous Leukemia, Ph1 Positive,Myelogenous Leukemias, Chronic,Myelogenous Leukemias, Ph1-Positive,Myeloid Leukemia, Ph1 Positive,Myeloid Leukemia, Philadelphia Positive,Myeloid Leukemias, Chronic,Myeloid Leukemias, Ph1-Positive,Myeloid Leukemias, Philadelphia-Positive,Ph1-Positive Myelogenous Leukemia,Ph1-Positive Myelogenous Leukemias,Ph1-Positive Myeloid Leukemia,Ph1-Positive Myeloid Leukemias,Philadelphia-Positive Myeloid Leukemia,Philadelphia-Positive Myeloid Leukemias
D016044 Fusion Proteins, bcr-abl Translation products of a fusion gene derived from CHROMOSOMAL TRANSLOCATION of C-ABL GENES to the genetic locus of the breakpoint cluster region gene on chromosome 22. Several different variants of the bcr-abl fusion proteins occur depending upon the precise location of the chromosomal breakpoint. These variants can be associated with distinct subtypes of leukemias such as PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; and NEUTROPHILIC LEUKEMIA, CHRONIC. Oncogene Protein p190(bcr-abl),Oncogene Protein p210(bcr-abl),bcr-abl Fusion Protein,bcr-abl Fusion Proteins,Bcr-Abl Tyrosine Kinase,Oncogene Protein p185(bcr-abl),Oncogene Protein p230(bcr-abl),p185(bcr-abl) Fusion Proteins,p190(bcr-abl) Fusion Proteins,p210(bcr-abl) Fusion Proteins,p230(bcr-abl) Fusion Proteins,Bcr Abl Tyrosine Kinase,Fusion Protein, bcr-abl,Fusion Proteins, bcr abl,Kinase, Bcr-Abl Tyrosine,Protein, bcr-abl Fusion,Tyrosine Kinase, Bcr-Abl,bcr abl Fusion Protein,bcr abl Fusion Proteins
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein

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